five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of [prostate cancer-specific mortality] at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks.

They also claim that

This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease.

However, the authors are clear that this new set of risk criteria will need to be validated against other sets of patient data before it could be adopted, and whether it is actually “better” than the current set of five risk criteria defined by the National Comprehensive Cancer Network (NCCN) is also an unanswered question. An editorial commentary by Carlsson and Kattan is also highly relevant to the appreciation of this paper.

Gnanapragasam et al. define their five risk strata as follows:

Risk stratum 1 (lowest risk level)

A Gleason score of 3 + 3 = 6 [ISUP prognostic risk 1] and a PSA level of < 10 ng/ml and a clinical stage of T1 or T2

Risk stratum 2

A Gleason score of 3 + 4 = 7 [ISUP prognostic risk 2] and a clinical stage of T1 or T2 (but a PSA level of < 10 ng/ml) or

A PSA level of 10 to 20 ng/ml and a clinical stage of T1 or T2 (but a Gleason score of 3 + 3 = 6)

Risk stratum 3

A Gleason score of 3 + 4 = 7 [ISUP prognostic risk 2] and a PSA level of 10 to 20 ng/ml and a clinical stage T1 or T2 or

Gnanapragasam et al. developed and internally validated their proposed risk strata using data from > 10,000 patients in the UK. It is clear that this new stratification system does potentially provide a very sound way to divide men into risk groups. However, the degree to which it will be a good method for making decisions about the need for treatment is harder to determine. While one might be justified in taking the position that anyone in risk stratum 1 could and should just be monitored, and that anyone in risk stratum 5 would need immediate treatment, the management of men in risk strata 2, 3, and 4 are harder to make absolute decisions about without taking a range of other factors into consideration, including things like the patient’s “biological” (as opposed to calendar) age, his life expectancy, the amount of cancer in the prostate, potentially the PSA density, and other factors.

As Carlsson and Kattan are careful to observe, however, the real question for all patients (and their clinicians) is still, “What is the long-term risk of prostate cancer mortality with treatment compared to risk of death from other causes?”

Are we getting better at making good predictions about the value of treatment as opposed to observation in carefully identified and selected patients? Sure we are. Have we reached a point at which we can tell 90 percent of patients that they will or won’t die of prostate cancer if they do or don’t get immediate treatment for localized disease? No. Not yet.

One Response

I would note that their risk strata 1-3 are pretty much identical to current NCCN strata called low-risk, favorable intermediate-risk, and unfavorable intermediate-risk. Other than the NCCN “very low risk” and “very high risk” substrata, where this system departs from NCCN is in giving Gleason 8 essentially its own stratum. Gleason 8 (ISUP grade group 4) may be Gleason scores of 4 + 4, 3 + 5, or 5 + 3. Some recent studies have called this “lumping together” into question. Mahal et al., looking at prostate cancer-specific mortality in the SEER database, found that 4 + 4 and 3 + 5 were similar, and that 5 + 3 was more similar to a Gleason 9 than those other Gleason 8s. Huynh et al., looking at data from radiation-treated patients at the Chicago Prostate Cancer Center, found that any pattern 5 predicted significantly worse survival outcomes. However, other groups, looking at data from their own institutions, found no significant difference (see for example this link and this one). Clearly, this requires more study.

I also wanted to comment on how RP-biased all the popular risk stratification systems are. That is only natural because most men are treated initially with RP, and the endpoints, whether biochemical recurrence or prostate cancer-specific survival, occurred after treatments beginning with prostatectomy for most men in these studies. We recently looked at an attempt to develop a risk stratification system based on the outcomes of radiation therapy. I think the questions I raised there are worth repeating:

• The D’Amico/NCCN risk stratification system is based on antiquated data and a small dataset for radiation. Is it time for a do-over?
• Do we have to have a single risk stratification system against which all therapies should be assessed? It certainly facilitates comparisons between therapies if we have a single system. However, different risk factors (e.g., age and percentage of positive cores) may be important in determining the risk associated with one therapy but not another.
• At what point has our ability to measure risk factors changed enough that the entire stratification system should be altered? The ability of multiparametric MRIs and advanced PET scans to more accurately assess stage and to target biopsy cores to more suspicious areas may increase the detected risk beyond what it was when the system was first set. Also, the Gleason scoring system and the AJCC staging system have both changed over the years.
• How do we maintain comparability with older clinical trials and with our databases if we change our risk stratification? Many trials were established a decade or more ago with pre-set risk groups. When the data mature, will they be hard to analyze? A similar effect occurred when biochemical recurrence after radiation was redefined by the Phoenix consensus in 2005. In many studies, both definitions were presented for a while.
• Can a stratification system from Europe gain acceptance in the US and particularly by the NCCN? How do we get widespread agreement on which system is the “gold standard.” As far as I know, the CAPRA Score is only used by UCSF, even though it is an NCCN member.
• What is the role of other biochemical measures? The Prostate Health Index or phi, 4KScore, PCA3, Oncotype Dx, and Prolaris tests all measure risk. Should any of them be used in a risk stratification system? Should first-degree relatives who have had prostate cancer be included as a risk factor? What about African Americans? And how should PSA be counted when the patient is taking a 5-reductase inhibitor (e.g., finasteride/Proscar or dutasteride/Avodart) for benign prostatic hyperplasia?

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